Long-term low-salt and high-salt diets differentially disrupt the gut-metabolite-brain axis and induce cognitive impairment

Long-term high-salt diets (HSD) are known to impair cognitive function, whereas the effects of low-salt diets (LSD) remain less well characterized. Here, we systematically compared the long-term effects of LSD and HSD on cognitive function and alterations along the gut-metabolite-brain axis under the same humanized microbiota background. We found that both long-term LSD and HSD induced cognitive impairment in humanized control (HC) mice, but were associated with distinct biological patterns. Both LSD and HSD impaired working and recognition memory and reduced hippocampal synaptic proteins. They also altered gut microbiota composition and decreased propionate and butyrate levels. Notably, HSD were additionally associated with increased pro-inflammatory microbial taxa, elevated circulating inflammatory cytokines, and broad lipid metabolic alterations. In contrast, cognitive impairment under LSD occurred in the absence of detectable systemic inflammation and was more specifically associated with reduced microbial metabolic output, including further decreases in acetate and isobutyrate. Our findings suggest that excessive salt restriction is not biologically equivalent to normal intake and may represent a distinct biological risk pattern for cognitive impairment, highlighting the importance of balanced dietary salt intake.